1. Field of the Invention
The present invention relates generally to the generation of libraries of chemical entities having defined physical, chemical or bioactive properties. More specifically, the invention provides libraries of compounds that possess a common core structure (scaffold) having diverse moieties attached to the scaffold.
2. Related Art
Conventionally, new chemical entities with useful properties are generated by identifying a chemical compound (called a "lead compound") with some desirable property or activity, creating variants of the lead compound, and evaluating the property and activity of those variant compounds. Examples of chemical entities with useful properties include paints, finishes, plasticizers, surfactants, scents, flavorings, and bioactive compounds, but can also include chemical compounds with any other useful property that depends upon chemical structure, composition, or physical state. Chemical entities with desirable biological activities include drugs, herbicides, pesticides and veterinary products. There are a number of flaws with this conventional approach to lead generation, particularly as it pertains to the discovery of bioactive compounds.
Historically, and presently, most novel pharmaceutical leads are obtained by screening large numbers of chemical entities. Some of these chemical entities are natural products while others are from synthetic compound collections. Rapid developments in molecular biology have provided many new therapeutic targets against which leads can be developed. Researchers are utilizing their recently acquired rapid robotic, high-throughput biological screening capability to search for leads within existing compound libraries for these biological targets. However, there are certain drawbacks in searching for leads within historically-collected compound libraries and natural product mixtures. Historically-collected compound libraries of pharmaceutical companies provide limited chemical and structural diversity. Lead identification and optimization from natural product mixtures remains a tedious and expensive process. To expand the molecular diversity against which high throughput screening could be carried out for lead identification, large biological and synthetic peptide combinatorial libraries (Gallop, M. A. et al., J. Med. Chem. 37:1233-1251 (1994); Pinilla, C. et al., Biopolymers (Pept. Sci) 37:221-240 (1995); Jung, G. et al., Chem., Int. Ed. Engl. 31:367-383 (1992); Dower, W. J. et al., Annu. Rep. Med. Chem. 26:271-280 (1991)), peptidomimetic combinatorial libraries (Zuckermann, R. N. et al., J. Med. Chem. 37:2678-2685 (1994); Moran, E. J. et al., Biopolymers (Pept. Sci.) 37:213-219 (1995)) and oligonucleotide combinatorial libraries (Ecker, D. J. et al., Nucleic Acids Res. 21:1853-1856 (1993); Gold, L. et al., Annu. Rev. Biochem. 64:763-797 (1995)) have been generated. However leads obtained from these linear polymer libraries usually have poor oral activity and rapid in vivo clearance (Smith, A. B. et al., J. Med. Chem. 37:215-218 (1994)). Consequently, converting these leads into orally active pharmaceutically useful drugs has met with limited success.
To overcome these limitations, nonoligomeric, low molecular weight synthetic libraries containing thousands of compounds have been generated. Some of these libraries have been synthesized as combinatorial mixtures while others were generated as single molecules by rapid parallel synthesis. See, for example, a benzodiazepine library generated by solid phase synthesis, which contains inhibitors of pp60s-src tyrosine kinase and ligands that block an autoimmune DNA-antibody interaction implicated in systemic lupus erythematosus (Bunin, B. A. and Ellman, J. A., J. Am. Chem. Soc. 114:10997-10998 (1992)), a diketopiperazine library containing ligands for the neurokinin-2 receptor (Gordon, D. W. and Steele, J., BioMed. Chem. Lett. 5:47-50 (1995)), and a pyrrolidine library containing a highly potent angiotensin-converting enzyme inhibitor (Murphy, M. M. et al., J. Am. Chem. Soc. 117:7029-7030 (1995)). See also, small molecule libraries of isoquinolinones (Goff, D. A. and Zuckermann, R. N., J. Org. Chem. 60:5748-5749 (1995)), dihydro- and tetrahydroisoquinolines (Meutermans, W. D. F. and Alewood, P. F., Tetrahedron Lett. 36:7709-7712 (1995)), and hydantoins (DeWitt, S. H. et al., Proc. Natl. Acad Sci. U.S.A. 90:6909-6913 (1993)). Even though in many cases further chemical modification of leads obtained from these small molecular libraries may be necessary to convert them into pharmaceutically useful drugs, this would be a more tractable task than optimizing a peptide or an oligonucleotide lead.
Among the greatest challenges in drug discovery is the conversion of peptide lead molecules with intermediate potency into high potency, non-peptide compounds with pharmacological properties that are appropriate for use as drugs. Recent advances in this effort have been the discovery of nonpolar, nonpeptide surrogates for peptide residues that have many of the characteristics desirable in a drug: low molecular weight, limited hydrophilicity and few or no chiral centers. For example, direct substitution of the RGD epitope, Arg-Gly-Asp-Trp (FIG. 4, i) with structurally rigid aromatic residues has provided several potent antagonists of the IIb/IIIa receptor (FIG. 4, ii) (Hartman et al., J. Med. Chem. 35:4640-4642 (1992)) and (FIG. 4, iii) (Alig et al., European Patent Application EP 0372486, 1990). In another example, inhibitors of the Ras Farnesyl transferase have been discovered in which the three C-terminal residues of a Cys-Val-IIe-Met lead (FIG. 4, iv) (Qian et al. J. Med. Chem. 4:2579-2584 (1994)) are replaced with a substituted biphenyl system (FIG. 4, v) (Qian et al. J. Med. Chem. 39:217-223 (1996)). Finally, thrombin inhibitors have been developed in which the central residue of D-Phe-Pro-descarboxy-Arg (FIG. 4, vi) is replaced with rigid orcinol group (FIG. 4, vii) (Von Der Saal, W., WO 94/20467).
Even though small molecule compound libraries have been generated to date, there exists a vast array of unexplored structural and chemical diversity that can be harnessed and utilized in the drug discovery process. In order to achieve this goal, there remains an urgent need to expand the solid phase chemistry methods for the preparation of low molecular weight, non-peptide compound libraries.
Dankwardt et al., Combinatorial Synthesis of Small-Molecule Libraries Using 3-Amino-5-hydroxybenzoic Acid, Molecular Diversity (1996) discloses the formation of a library of small organic molecules. The method and library utilizes 3-amino-5-hydroxybenzoic acid as the underlying core structure. The hydroxy group in the 5-position has a major influence on the types of compounds that can ultimately be prepared in the resulting library.
PCT published application WO 95/02566 describes a multiple component combinatorial array synthesis of compounds that share a common core structure and have at least three components.
U.S. Pat. No. 5,288,514 describes a solid phase combinatorial synthesis of benzodiazepine compounds.
PCT published application WO 95/16712 describes the use of silane chemistry and linkers in combinatorial syntheses of non-peptide compounds. The compounds are screened as pharmaceutical agents by screening for G-protein coupled receptor binding, enzyme inhibition and ability to block channels through cell membranes.
A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states. The methods and libraries of the present invention offer a convenient and efficient way of developing lead compounds for modulating the activity of proteases and other therapeutically-relevant enzymes or receptors.